Back to EveryPatent.com
United States Patent |
5,238,687
|
Magruder
,   et al.
|
August 24, 1993
|
Delivery device with a protective sleeve
Abstract
This invention relates to an active agent delivery device. More
particularly, the invention relates to a delivery device that includes a
sleeve to protect the delivery device from transient mechanical forces.
The delivery device of the invention is robust and resistant to transient
mechanical forces. The invention provides a fluid-imbibing delivery device
comprising a housing enclosing an internal compartment, said housing
having a first wall section that substantially restricts the passage of
fluid into the delivery device, i.e. is substantially fluid-impermeable,
and that contains a beneficial agent; a second wall section that permits
the passage of fluid into the delivery device, i.e. is fluid-permeable,
and that contains at least one expandable driving member; and exit means;
with a protective sleeve means extending from the first wall section of
the housing to cover and protect the second wall section of the housing
and the junction of the first and second sections. The protective sleeve
is preferably configured to provide substantially no resistance to flow of
fluid-vapor through the fluid-permeable second wall section.
Inventors:
|
Magruder; Judy A. (Mountain View, CA);
Peery; John R. (Palo Alto, CA);
Eckenhoff; James B. (Los Altos, CA)
|
Assignee:
|
Alza Corporation (Palo Alto, CA)
|
Appl. No.:
|
939186 |
Filed:
|
September 2, 1992 |
Current U.S. Class: |
424/473; 424/422; 424/423; 424/438; 604/890.1 |
Intern'l Class: |
A61K 009/24 |
Field of Search: |
424/473
|
References Cited
U.S. Patent Documents
2779241 | Jun., 1954 | Howard | 89/1.
|
3732865 | May., 1973 | Higuchi et al. | 128/260.
|
3845761 | Nov., 1974 | Zaffaroni | 128/130.
|
3845770 | Nov., 1974 | Theeuwes et al. | 128/260.
|
3854480 | Dec., 1974 | Zaffaroni | 128/260.
|
3865108 | Feb., 1975 | Hartop | 128/260.
|
3896819 | Jul., 1975 | Zaffaroni | 128/130.
|
3916899 | Nov., 1975 | Theeuwes et al. | 128/260.
|
3995632 | Dec., 1976 | Nakano et al. | 128/260.
|
4002173 | Jan., 1977 | Manning et al. | 128/296.
|
4063064 | Dec., 1977 | Saunders et al. | 219/121.
|
4077407 | Mar., 1978 | Theeuwes et al. | 128/260.
|
4088864 | May., 1978 | Theeuwes et al. | 219/121.
|
4111202 | Sep., 1978 | Theeuwes | 128/260.
|
4111203 | Sep., 1978 | Theeuwes | 128/260.
|
4160020 | Jan., 1979 | Ayer et al. | 424/15.
|
4200098 | Nov., 1980 | Ayer et al. | 128/260.
|
4203439 | May., 1980 | Theeuwes | 128/260.
|
4207893 | Jun., 1980 | Michaels | 128/260.
|
4235236 | Nov., 1980 | Theeuwes | 128/260.
|
4285987 | Aug., 1981 | Ayer et al. | 427/3.
|
4309996 | Jan., 1982 | Theeuwes | 128/260.
|
4320759 | Mar., 1982 | Theeuwes | 128/260.
|
4327725 | May., 1982 | Cortese et al. | 128/260.
|
4526938 | Jul., 1985 | Churchill et al. | 525/415.
|
4612008 | Sep., 1986 | Wong et al. | 604/892.
|
4855141 | Aug., 1989 | Eckenhoff et al. | 424/423.
|
4874388 | Oct., 1989 | Wong et al. | 604/891.
|
4969884 | Nov., 1990 | Yum | 604/892.
|
5034229 | Jul., 1991 | Magruder et al. | 424/422.
|
5057318 | Oct., 1991 | Magruder | 424/438.
|
5059423 | Oct., 1991 | Magruder | 424/438.
|
Foreign Patent Documents |
373867 | Jun., 1990 | EP.
| |
Primary Examiner: Page; Thurman K.
Assistant Examiner: Phelan; D. Gabrielle
Attorney, Agent or Firm: Larson; Jacqueline S., Stone; Steven F., Mandell; Edward L.
Parent Case Text
This application is a division of application Ser. No. 07/551,720, filed
Jul. 11, 1990, now U.S. Pat. No. 5,180,591 and benefit of the filing date
of said earlier filed application is claimed under 35 U.S.C. .sctn. 120.
Claims
What is claimed is:
1. A fluid-imbibing dispenser for delivering a beneficial agent to an
animal, the dispenser comprising:
(a) a first wall section comprising a wall that surrounds an internal
compartment and an open end;
(b) a second wall section comprising a wall that surrounds an internal
compartment and an open end, the wall comprising a composition permeable
to the passage of fluid, wherein the open end of the first wall section
and the open end of the second wall section are in mated contact;
(c) a rigid sleeve extending from the first wall section to cover the
junction of the first wall section and the second wall section and to at
least partially cover the sides of the second wall section, the inside
diameter of the sleeve being greater than the outside diameter of the
second wall section, and the sleeve being able to resist transient
mechanical forces of at least about 2 kilograms force;
(d) a beneficial agent in the compartment comprising the first wall
section;
(e) at least one expandable driving member in the compartment comprising
the second wall section for pushing the beneficial agent from the
compartment;
(f) a partition layer substantially impermeable to fluid between the
beneficial agent and the expandable member; and
(f) exit means for delivering the beneficial agent to the animal.
2. A dispenser according to claim 1 wherein the exit means comprises an
exit passageway and means for closing the exit passageway.
3. A dispenser according to claim 2 wherein the means for closing the exit
passageway is a break-off tab.
4. A dispenser according to claim 2 wherein the means for closing the exit
passageway is a material which get discharged, leaches or erodes.
5. A dispenser according to claim 1 wherein the sleeve resists transient
mechanical forces of about 6 kilograms force.
6. A dispenser according to claim 1 wherein the sleeve has a minimum
tensile strength of about 9000 psi.
7. A dispenser according to claim 1 wherein the sleeve completely covers
the sides of the second wall section and extends to or below the rear end
of the second wall section.
8. A dispenser according to claim 1 wherein the sleeve further comprises a
plurality of ridges on its inner circumference.
9. A dispenser according to claim 1 wherein the sleeve further comprises a
plurality of fluid or fluid vapor passage means.
10. A dispenser according to claim 1 which comprises 2 or 3 driving
members.
11. A dispenser according to claim 10 wherein the driving members comprise
an osmopolymer together with an osmagent.
12. A dispenser according to claim 1 wherein the open end of the first wall
section is enlarged and the open end of the second wall section is placed
in the open enlarged end of the first wall section.
13. A dispenser according to claim 1 wherein the animal is a swine or a
bovine.
14. A dispenser according to claim 1 wherein the beneficial agent is a
hormone.
15. A dispenser according to claim 1 wherein the first wall section is
impermeable to the passage of fluid, and the beneficial agent is a
somatotropin, a somatotropin derivative or a somatotropin analogue.
16. A dispenser according to claim 1 wherein the animal is a hog and the
beneficial agent is porcine somatotropin.
17. A dispenser according to claim 1 which is an implant.
18. A dispenser according to claim 16 wherein the dispenser is an implant.
19. A dispenser according to claim 18 wherein there are two expandable
driving members; the exit means comprises an exit passageway and means for
closing the exit passageway; the means for closing the exit passageway is
a material which gets discharged, leaches or erodes; and the sleeve
resists transient mechanical forces of from about 2 kilograms force to
about 6 kilograms force.
20. A dispenser according to claim 19 wherein the sleeve completely covers
the sides of the second wall section and extends to or below the rear end
of the second wall section.
21. A dispenser according to claim 20 wherein the sleeve further comprises
a plurality of ridges on its inner circumference.
22. A method for delivering a beneficial agent to an animal, wherein the
method comprises:
(1) admitting into the animal a dispenser comprising:
(a) a first wall section comprising a wall that surrounds an internal
compartment and an open end;
(b) a second wall section comprising a wall that surrounds an internal
compartment and an open end, the wall comprising a composition permeable
to the passage of fluid, wherein the open end of the first wall section
and the open end of the second wall section are in mated contact;
(c) a rigid sleeve extending from the first wall section to cover the
junction of the first wall section and the second wall section and to at
least partially cover the sides of the second wall section, the inside
diameter of the sleeve being greater than the outside diameter of the
second wall section, and the sleeve being able to resist transient
mechanical forces of at least about 2 kilograms force;
(d) a beneficial agent in the compartment comprising the first wall
section;
(e) at least one expandable driving member in the compartment comprising
the second wall section for pushing the beneficial agent from the
compartment; and
(f) exit means for delivering the beneficial agent to the animal;
(2) allowing fluid to be imbibed through the permeable second wall section
of the dispenser for causing the expandable driving member or members to
increase in volume; and
(3) delivering the beneficial agent to the animal by the driving member of
members increasing in volume and occupying space in the compartment
comprising the first wall section, thereby pushing the beneficial agent
through the exit means to the animal.
23. A method according to claim 22 wherein the sleeve resists transient
mechanical forces of about 6 kilograms force.
24. A method according to claim 22 wherein the sleeve has a minimum tensile
strength of about 9000 psi.
25. A method according to claim 22 wherein the sleeve completely covers the
sides of the second wall section and extends to or below the rear end of
the second wall section.
26. A method according to claim 22 wherein the sleeve further comprises a
plurality of ridges on its inner circumference.
27. A method according to claim 22 wherein the sleeve further comprises a
plurality of fluid or fluid vapor passage means.
Description
FIELD OF THE INVENTION
This invention relates to an active agent delivery device. More
particularly, the invention relates to a delivery device that is robust
and resistant to transient mechanical forces.
BACKGROUND OF THE INVENTION
Delivery devices for administering a beneficial agent to a biological fluid
environment of use are known in the prior art. Representative examples of
various types of delivery devices are disclosed in U.S. Pat. Nos.
3,845,770; 3,916,899; 3,995,632; 4,111,202; 4,111,203; 4,203,439;
4,327,725; and 4,612,008, which are incorporated herein by reference. The
delivery devices described in the above patents operate successfully for
their intended use and they can delivery many beneficial agents for their
intended effects. However, it has been observed that their use can be
limited because they lack the necessary elements to delivery beneficial
agents that are sensitive to fluids and to fluids containing biological
gases. Their use may be limited because beneficial agents that are
sensitive to such aqueous biological fluids or to other fluids external to
the delivery device may be adversely affected by fluids that enter the
device and contact the beneficial agents during operation of the device.
Examples of such fluid-sensitive agents include proteins, peptides, and
hormones. Moreover, the prior art devices lack the necessary means for
their use as implant devices for dispensing such sensitive agents to a
biological fluid-rich environment of use.
To overcome the limitations associated with the prior art delivery devices,
a delivery device has been developed and is described and claimed in
copending, commonly-assigned U.S. Pat. No. 5,034,229, filed Dec. 13, 1988,
to Magruder et al. for Delivery System Comprising Means for Governing
Fluid Ingress into the System, the entire disclosure of which is
incorporated herein by reference. This delivery device comprises a
compartment, one portion of which is impermeable to fluid and contains a
fluid-sensitive drug protected from a fluid environment and a second
portion of which is permeable to fluid and contains an expandable driving
member for administering the drug to the fluid environment of use. The
system has been found to be particularly useful as an implant in livestock
for delivering a fluid-sensitive drug over a broad range of dosage
delivery rates according to a predetermined time-release pattern.
Although in vitro tests and in vivo tests on isolated animals indicated
satisfactory system performance, in vivo tests under field conditions of
the delivery device of U.S. Pat. No. 5,034,229 in livestock demonstrated
an undesirably high failure rate, either by failing to deliver the
beneficial drug at the desired rates or by failing to deliver the required
dosage of the drug or by the fluid-sensitive drug coming into contact with
fluid prematurely and becoming adversely affected prior to its delivery
into the fluid environment of the host animal. The discrepancy between in
vivo tests on isolated animals and on animals under field conditions was
totally unexpected, not readily explained, and could adversely affect the
commercialization of the delivery device.
SUMMARY OF THE INVENTION
It has now been discovered by the inventors that the failure of the devices
of U.S. Pat. No. 5,034,229 under field conditions was attributable to
damage to the portion of the compartment containing the expandable driving
member or damage to the junction between the permeable and impermeable
portions of the compartment as a result of radially applied transient
mechanical forces, which forces are the result of such actions as the
implant procedure itself; behavior patterns of the host animals, such as
animal-to-animal interaction which is often violent, and collisions of the
animals into guardrails of pens or other structures; and miscellaneous in
vivo forces which act upon the implanted delivery device. It was also
discovered that the frequency of failure could be greatly reduced if these
delivery devices were rendered more robust and resistant to such transient
mechanical forces in a manner that does not interfere with delivery of the
protected beneficial agent at a controlled rate.
Accordingly, it is desirable to provide a delivery device that is robust
and resistant to mechanical forces in vivo and does not interfere with the
in vivo delivery of a beneficial agent.
Therefore, the present invention provides a fluid-imbibing delivery device
comprising a housing enclosing an internal compartment, said housing
having a first wall section that substantially restricts the passage of
fluid into the delivery device, i.e. is substantially fluid-impermeable,
and that contains a beneficial agent; a second wall section that permits
the passage of fluid into the delivery device, i.e. is fluid-permeable,
and that contains at least one expandable driving member; and exit means;
with a protective sleeve means extending from the first wall section of
the housing to cover and protect the second wall section of the housing
and the junction of the first and second sections. The protective sleeve
is preferably configured to provide substantially no resistance to flow of
or fluid vapors through the fluid-permeable second wall section.
It has now been found that the placement of a protective sleeve of
sufficient strength onto the delivery device of U.S. Pat. No. 5,034,229
and extending from the substantially impermeable first wall section of the
device over and around the sides of the water-permeable second wall
section and over the junction of the two wall sections provides sufficient
protection to the delivery device so that the device does not break or
otherwise become nonfunctional or malfunctional as a result of transient
mechanical forces.
The protective sleeve of the present invention is of a sufficiently high
tensile strength and rigidity to resist transient mechanical forces of
about two kilograms or more. The inside diameter of the sleeve is greater
than the outside diameter of the permeable portion of the compartment to
allow access to environmental or fluid vapors to the surface area of the
permeable compartment portion. The sleeve may be integral with the first
wall section or it may be a separate entity that is attached to the first
wall section. The length of the sleeve may extend to cover in part or
totally the sides of the second wall section. The sleeve may further
comprise a plurality of fluid or fluid vapor passage means which
facilitate ventilation of air from the annular space between the sleeve
and the permeable portion of the compartment wall during the implant
procedure and which facilitate access of the environmental fluid to the
permeable wall.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an opened view of one embodiment of the delivery device of the
invention, illustrating one structural embodiment of the delivery system
comprising a first walled section and a second walled section, where the
sleeve of the invention extends from and is integral with the first walled
section to protectively cover the second walled section.
FIG. 2 is an opened view of another embodiment of the delivery device of
the invention, depicting a delivery system comprising a beneficial agent
section and a driving member section joined as engaging structural member
sections with a separate sleeve section extending from the beneficial
agent section to protectively cover the driving member section and the
junction of the two sections.
FIG. 3 is a partial opened view of a delivery device of the invention
showing in greater detail the protective sleeve section in relation to the
beneficial agent section and the driving member section of the device.
FIG. 4 is a partial opened view of another delivery device of the
invention.
FIG. 5 is an opened view of a protective sleeve of the present invention
prior to installation on a delivery device.
FIG. 5A is a cross-sectional view through line A--A of the protective
sleeve of FIG. 5.
FIG. 6 is a partial exterior view of a delivery device of the invention
showing a protective sleeve of the present invention.
FIG. 7 is an exterior view of another delivery device of the invention
wherein the delivery device includes a protective sleeve comprising a
plurality of ribs.
DETAILED DESCRIPTION OF THE INVENTION
In the following discussion, like reference numerals refer to like elements
in the figures.
FIG. 1 depicts in opened view one embodiment of the delivery device
according to the present invention. Delivery system 10 of FIG. 1 comprises
a housing 11 formed of a wall 12, which wall 12 comprises a first wall
section 12a and a second wall section 12b. Wall 12, comprising first wall
section 12a and second wall section 12b, surrounds and defines an internal
compartment 18. Delivery system 10 has at least one exit passageway 13 for
delivering a beneficial agent formulation from delivery system 10.
Optionally, the exit passageway can be occluded with a material that gets
discharged, leaches or erodes during the time of use. In FIG. 1, delivery
system 10 comprises a dome-shaped rear end 8 and a similar dome-shaped
lead end 9 for aiding in placing delivery system 10 in an animal host. In
an embodiment not shown, delivery system 10 can be manufactured with a
pair of flat ends 8 and 9. The term "lead end", as used herein, generally
denotes the end from which beneficial agent is released from the system.
In use, either the lead end or the rear end may be implanted first.
Delivery system 10 also comprises a rigid protective sleeve 30 surrounding
a portion of housing 11 to rear end 8; sleeve 30 may, optionally, extend
below rear end 8. Wall section 12a defines lead end 9, if forms passageway
13 and it surrounds that portion of internal compartment area 18 that
contains a beneficial agent formulation. Wall section 12a at its end
distant from lead end 9 defines and forms receiving means 19 and
protective sleeve 30. Receiving means 19 is enlarged slightly for
receiving second wall section 12b. Protective sleeve 30 is tubular in
shape with an opening 34 and extends from the receiving means 19 down to
cover the sides of second wall section 12b, providing a space 32 that is
defined by the inner wall surface of sleeve 30 and the outer surface of
wall 12b and is open to the environment at opening 34. Wall section 12b
surrounds that portion of internal compartment area 18 that contains a
means for expanding and for occupying space in compartment 18 for delivery
of a beneficial agent formulation from delivery system 10. The two wall
sections, sections 12a and 12b, at receiving means 19 are close in size
and they form a tight friction fit therebetween. There is clearance or
tolerance in size to allow wall section 12b a sliding movement into the
receiving means 19 of wall section 12a. Wall section 12a and wall section
12b can be telescoped completely into a closed and continuous internal
walled position. Optionally, they can be held together by heat fusion, by
an adhesive, or the like.
First wall section 12a comprises a composition that is substantially
impermeable to the exchange of fluid, beneficial agent and other
ingredients contained in delivery system 10. Wall section 12a, in a
presently preferred manufacture, is substantially impermeable to the
ingress of an external fluid to serve as a means for substantially
protecting a beneficial agent that is sensitive to fluid from an exterior
fluid present in the environment of use. Wall section 12a substantially
restricts and prevents fluid from passing through wall 12a and entering
into compartment 18 in the region containing a beneficial agent
formulation. Furthermore, wall section 12a, at least in the area
comprising the protective sleeve 30, is of a composition that has an
adequate tensile strength, thickness and rigidity to withstand transient
mechanical forces in excess of about 2 kg.sub.f in order to protect wall
section 12b and the junction of sections 12a and 12b at receiving means 19
from such forces. Second wall section 12b is permeable to the passage of
fluid and it is substantially impermeable to the passage of other
ingredients contained in delivery system 10. Wall sections 12a and 12b
optionally comprise a plasticizer that imparts flexibility and workability
to the wall. Wall 12, comprising sections 12a and 12b, is nontoxic and, in
a preferred embodiment, it maintains its physical and chemical integrity;
that is, wall 12 does not erode during the dispensing period.
Compartment 18 comprises a beneficial agent formulation, which beneficial
agent formulation comprises a beneficial agent 20, identified by dots, and
a pharmaceutically acceptable carrier 21, identified by wavy lines. The
pharmaceutically acceptable carrier in one presently preferred embodiment
comprises more than one ingredient, such as a buffer 22, identified by
horizontal dashes; an pharmaceutically acceptable vehicle 23, identified
by vertical lines; a pharmaceutically acceptable surfactant 24, identified
by slanted lines; and other formulation ingredients, as are known in the
art. Compartment 18 further comprises an expandable driving member 25,
identified by slanted lines. Expandable driving member 25 optionally
comprises an osmagent 26, identified by dots, homogeneously or
heterogeneously blended with expandable driving member 25. Compartment 18
optionally comprises a partition layer 27, represented by horizontal
lines, which layer 27 is positioned between the beneficial agent
formulation and the expandable driving member 25. Partition layer 27, in a
presently preferred embodiment, comprises a composition that is
substantially impermeable to the passage of fluid, and it serves to
restrict the passage of fluid present in the expandable driving member
into the beneficial agent formulation. It operates to essentially maintain
the integrity of the beneficial agent layer and the driving member layer.
Partition layer 27 acts also to insure that the expanding driving force
generated by the expandable driving member 25 is applied directly against
the beneficial agent formulation. In operation, as the expandable member
25 absorbs and imbibes fluid through second wall section 12b from the
environment of use, it expands and pushes against partition layer 27,
causing it to slide inside compartment 18. Partition layer 27 moves
towards exit passageway 13, pushing the beneficial agent formulation
through passageway 13 for maximizing the delivery of the beneficial agent
to a biological environment of use, such as livestock.
FIG. 2 is in opened view another embodiment of the delivery device of the
invention. In FIG. 2, delivery device 10 comprises housing 11 formed by
wall 12. Wall 12 comprises a first wall section 12a of fluid-impermeable
composition that surrounds that portion of internal compartment 18
containing a beneficial agent, and a second wall section 12b of
fluid-permeable composition that surrounds that portion of internal
compartment 18 containing at least one means for expanding and for
occupying space in the compartment for delivery of the beneficial agent.
First wall section 12a is provided with receiving means 19, and second
wall section 12b is provided with an opened end 7. First wall section 12a
is thinner at receiving means 19 to provide an enlarged open end for
slipping over or receiving second section 12b at its opened end 7, so that
second wall section 12b is telescopically capped by the engaging first
wall section 12a. The two sections can be joined together by various
techniques such as solvent weld, adhesive bond, thermal weld, ultrasonic
weld, spin weld, induction weld, or by similar welding or bonding
operations.
Delivery system 10 also comprises protective sleeve 30 which is joined with
first wall section 12a at a position over the junction of wall sections
12a and 12b at receiving means 19. Sleeve 30 is tubular in shape with an
opening 34 and extends over and around the sides of second wall section
12b. The thinner diameter of sleeve 30 is greater than the outer diameter
of second wall section 12b to provide a space 32. Space 32 allows fluid or
fluid vapor from the environment of use to come into contact with
fluid-permeable second wall section 12b. Protective sleeve 30 should be of
a material having a sufficiently high tensile strength, thickness and
rigidity to withstand transient mechanical forces in excess of about two
kg.sub.f in order to protect second wall section 12b and the junction of
sections 12a and 12b at receiving means 19 from such forces. Rigid
protective sleeve 30 can be joined to first wall section 12a by various
techniques such as solvent weld, adhesive bond, thermal weld, ultrasonic
weld, spin weld, induction weld, or by similar welding or bonding
operations.
Delivery device 10 in FIG. 2 further comprises lead end 9, rear end 8,
internal compartment 18, beneficial agent 20, pharmaceutically acceptable
carrier 21, pharmaceutically acceptable buffer 22, pharmaceutical
acceptable vehicle 23, and a pharmaceutically acceptable surfactant 24. In
a presently preferred embodiment, delivery device 10 comprises a plurality
of expandable driving members 25a and 25b initially housed in second wall
section 12b. This configuration is merely illustrative and there may be
any number of driving members present. Generally, there are from one to
five expandable driving members; however, this number is not controlling.
The expandable driving members in a presently preferred embodiment are
formed as depots or layers and comprise like or unlike compositions. For
example, driving members 25a and 25b can be made as tablets comprising
like osmopolymers or like osmagents, or they can comprise unlike
osmopolymers or unlike osmagents, or one or more of the members can be a
composition comprising an osmopolymer together with an osmagent. The
members can be the same or they can be different. The driving members can
be inserted through open end 7 successively into second wall section 12b.
Delivery device 10 in a presently preferred manufacture comprises
partition layer 27 that separates the beneficial agent formulation from
the expandable driving members, partition layer 27 being positioned at the
time of manufacture near receiving means 19 of first wall section 12a.
In FIG. 2, delivery device 10 further comprises break-off or severable tab
14 at lead end 9. Break-off or severable tab 14 covers exit passageway 13.
Tab 14 serves several purposes: it seals delivery device 10 to prevent
premature delivery of a beneficial agent from delivery device 10, it helps
maintain the clean or optionally sterile environment inside delivery
device 10, and it protects the ingredients inside the delivery device from
oxidation by air. Break-off tab 14 comprises an optional scored line (not
shown) to enhance its separation from the delivery device. Tab 14 is
easily snapped off at the time of use by manual pressure, by tapping, by
twisting, by filing, by cutting, or the like, to provide an exit
passageway. The break-off tab 14 can be formed during manufacture or it
can be joined to the housing 11 by heat fusion, adhesive joining or the
like. Optionally in combination with break-off tab 14, the exit passageway
can be occluded with material that gets discharged, leaches or erodes
during the time of use.
In one embodiment of delivery device 10 as illustrated in FIG. 2, the
system is manufactured as an implant comprising a body length of about
49.68 mm, a diameter of the first wall section of about 4.97 mm, a
diameter of the second wall section of about 4.09 mm, a diameter of the
protective sleeve of about 5.97 mm, a sleeve wall thickness of about 0.51
mm, a beneficial agent formulation occupying a length of 33.73 mm, a
partition layer occupying a space of 5.08 mm, and an initial total space
of 7.62 mm occupied by the expandable driving members. The optional
break-off tab is about 6.35 mm in length and when broken off forms an exit
passageway of 0.51 mm. Prior to placement in the receiving tissue, the
break-off tab can be broken off and the exit passageway can be occluded
with a material such as wax that gets discharged, leaches or erodes when
placed in the tissue. The implant can be implanted into receiving tissue
using an implanter. Generally, an implanter comprises a tubular member
with a central longitudinal axial bore, a pointed, elongated, annular
concavely beveled implanting end and an implant-charging end. The
implanting end and the charging end communicate through a bore. A plunger
adapted to be removably inserted in the bore is designed for slidable
movement therein for applying the necessary force for implanting the
implant. Also, the implant can be surgically implanted in the muscle or
other tissue or livestock.
FIGS. 3 and 4 are opened views of that portion of delivery device 10
encompassing the rigid protective sleeve 30, shown in greater detail.
Sleeve 30 is tubular in shape and is joined with first wall section 12a to
cover the junction of first wall section 12a and second wall section 12b
at receiving means 19. While sleeve 30 can cover only a portion of the
junction between the first and the second wall sections, in a presently
preferred embodiment, as illustrated in FIG. 3, sleeve 30 extends to cover
the entire thinner portion of first section 12a, that is, that portion
comprising receiving means 19 that slips over or receives open end 7 of
second section 12b. Sleeve 30 can optionally extend to cover a portion of
first section 12a beyond the thinner section, as illustrated in FIG. 4. In
this manner, the junction between first section 12a and second section
12b, which has been found by the inventors to be a point of weakness in
the delivery system, is reinforced by protective sleeve 30 against
transient mechanical forces to prevent breakage of the delivery system at
this point. Protective sleeve 30 and first wall section 12a can be joined
together by various techniques such as solvent weld, adhesive bond,
thermal weld, ultrasonic weld, spin weld, induction weld, or by similar
welding or bonding operations known in the art.
Tubular protective sleeve 30 extends down from receiving means 19 of first
section 12a to rear end 8 of delivery device 10, thus surrounding the
sides of second wall section 12b and protecting the wall section from
damage as a result of transient mechanical forces. The sleeve can extend
just to the end of rear end 8, or it can stop a short distance above rear
end 8, or preferably it extends slightly below rear end 8 as illustrated
in FIGS. 3 and 4. In a preferred embodiment, the length of sleeve 30
coincides with the end of rear end 8 when rear end 8 has undergone the
expansion that often occurs as a result of fluid imbibition. The
protective sleeve 30 may optionally be radiused or contoured to form a lip
36, as illustrated in FIG. 4, to partially cover and enclose rear end 8.
The inner diameter of the wall of sleeve 30 is greater than the outer
diameter of second section 12b, forming a space 32 between the two walls.
This space 32 is necessary for the proper functioning of the driving
member of members, 25a, 26b and 25c for example, housed within second
section 12b. In other words, space 32 allows fluid or fluid vapor from the
environment of use to come into contact with the fluid-permeable wall of
second section 12b through opening 34 of sleeve 30 in order to activate
the driving members. Space 32 should be of sufficient width to allow an
adequate supply of fluid or fluid vapor to come into contact with second
section 12b along its entire surface area. The width of the space 32
between sleeve 30 and second section 12b is, in a presently contemplated
embodiment, minimally about 0.0020 in. (0.051 mm) and preferably about
0.020 in. (0.51 mm).
In a presently preferred embodiment where protective sleeve 30 is a
separate entity from and not integral with first wall section 12a,
protective sleeve 30 comprises a ridge or ridges 38 on the inner wall
surface of the sleeve, as shown in FIGS. 3 and 4. This ridge 38 can be
continuous, extending around the entire inner circumference of sleeve 30,
or there can be a plurality of individual ridges spaced at intervals in
the same plane around the inner circumference of sleeve 30, such as ridges
38a, 38b, 38c and 38d as illustrated in FIGS. 5 and 5A. Ridge or ridges 38
are located in sleeve 30 so that, in the completed delivery device, they
rest against the end of receiving means 19 of first wall section 12a at a
point so that a portion of sleeve 30 extends to cover the junction of
first wall section 12a and second wall section 12b and the remainder of
sleeve 30 extends around the sides of second wall section 12b. While they
are not necessary to the protective function of the sleeve, ridge or
ridges 38 assist in the manufacturing process by providing a stop against
receiving means 19 when sleeve 30 is slipped onto wall section 12a, and
they can provide additional stability to the delivery device.
In a presently contemplated embodiment of the invention, protective sleeve
30 further comprises one or a plurality of fluid or fluid vapor passage
means, shown as holes 40a and 40b in FIGS. 5 and 6, through the wall of
the sleeve, which holes communicate with the outside environment of use
and with space 32 between sleeve 30 and second section 12b. These holes
facilitate ventilation of air from space 32 during the implant procedure
and provide another point of access to second section 12b for the fluid or
fluid vapor environment. The holes are preferably placed relatively closer
to receiving means 19 than to sleeve opening 34.
FIG. 7 shows an alternative embodiment of delivery device 10 of the present
invention. As seen in FIG. 7, system 10 comprises a housing 11 formed of a
wall 12 with a rear end 8 and lead end 9 with break-off tab 14. Wall 12
comprises a first wall section 12a and a second wall section 12b. First
wall section 12a has formed integrally therewith a protective sleeve 390
which comprises a plurality of ribs 30a, 30b, 30c and 30d extending down
over second wall section 12b and separated from each other by longitudinal
spaces 31a, 31b, 31c and 31d (of which, 31a and 31b are shown). These
ribs, 30a for example, provide protection from transient mechanical forces
for second wall section 12b while the longitudinal spaces, 31a for
example, allow the passage of fluid from the environment to come into
contact with second wall section 12b. The ribs, 30a for example, of the
protective sleeve extend from the receiving means 19 (not shown) down to
cover second wall section 12b, providing a space 32 that is defined by the
inner wall surface of the sleeve ribs, 30a for example, and the outer
surface of wall 12b and is open to the environment at opening 34 and
through longitudinal spaces 31a-31d.
In accordance with the practice of this invention, it has now been found
that device 10 can be manufactured with a rigid protective sleeve 30 that
at least partially surrounds the sides of second wall section 12b and the
junction of second wall section 12b and first wall section 12a. Protective
sleeve 30 comprises a composition that is nontoxic to animals and
livestock and is compatible with the environment of use. The material
comprising sleeve 30 is of a high tensile strength and a sufficient
thickness to withstand transient mechanical forces. It has been found that
the devices of U.S. Pat. No. 5,034,229, without the protective sleeve of
this invention, tend to become malfunctional or nonfunctional when a
transient mechanical force of about 2 kg.sub.f is radially applied to the
junction of the water-impermeable and the water-permeable wall portions.
Therefore, it is necessary that the protective sleeve be comprised of a
material of a strength sufficient to withstand transient mechanical forces
of at least about 2 kg.sub.f and preferably of at least about 6 kg.sub.f
of force. Usually, a material having a minimum tensile strength at yield
of about 9,000 psi is acceptable for use in the present invention. The
tensile strength may be lower, in which case the sleeve wall is thicker to
provide the necessary strength.
While the composition of the sleeve 30 may be of a semipermeable material,
so long as the material is of sufficient strength as required herein, in a
presently preferred embodiment the composition is of a material which is
substantially impermeable to fluids. Typical impermeable compositions for
forming protective sleeve 30 are vinylidene chloride copolymers and
terpolymers such as vinylidene chloride-vinyl chloride copolymer,
vinylidene chloride-acrylonitrile copolymer, vinylidene chloride-styrene
copolymer, and vinylidene chloride-vinyl chloride-acrylonitrile
terpolymer; acrylonitrile polymers such as acrylonitrile-methyl vinyl
ether copolymer, acrylonitrile-styrene copolymer,
acrylonitrile-butadiene-styrene terpolymer, and the like; halogenated
polymers such as chlorinated polyether, polytetrafluoroethylene,
polychlorotrifluoroethylene, tetrafluoroethylene and hexafluoropropylene
copolymer, polyvinylfluoride, polyvinylchlorobuteral, plasticized
polyvinylidene chloride, and the like; nylon; polyamide-imide;
polyarylether; polysulfone; polycarbonate; polyurethane; high density
polyethylene; polyvinylchloride-acrylic copolymer;
polycarbonate-acrylonitrile-butadiene-styrene; glass; bakelite; melamine;
polystyrene; polyacrylate; stainless steel and stainless steel mesh; and
the like. Polycarbonate and polysulfone are presently preferred. The
polymers are known in the Handbook of Common Polymers, by Scott and Roff,
CRC Press, Cleveland Rubber Co., Cleveland, Oh. Where the composition of
sleeve 30 comprises a semipermeable material, the semipermeable material
may be strengthened by the addition of rigid fillers, such as glass or
ceramic, for example.
First wall section 12a, which surrounds the internal space of compartment
18 initially occupied by the beneficial agent formulation, comprises a
composition that does not adversely affect the beneficial agent, the
osmopolymer, the osmagent, other ingredients in device 10, the host, or
the like. First wall section 12a comprises a composition comprising means
that substantially limits or prevents the passage of an external fluid
into device 10. The phrase, "substantially limits or prevents," as used
herein, indicates the volume of external fluid passing through first wall
section 12a is substantially negligible, that is, about zero up to about 1
.mu.l per day. Typical compositions for forming first section 12a are
chosen from the substantially impermeable compositions listed above for
protective sleeve 30 and may be the same as or different from the
composition making up the protective sleeve.
The second wall section 12b comprises a composition comprising means that
aids in controlling fluid flux into the compartment area occupied by the
expandable driving member. The composition is permeable to the passage of
external fluids such as water and biological fluids, and it is
substantially impermeable to the passage of beneficial agents,
osmopolymers, osmagents, and the like. Typical compositions comprising
semipermeable materials for forming wall 12b are known in the art. In one
presently preferred embodiment, they are a member selected from the group
consisting of a cellulose ester, a cellulose ether and a cellulose
ester-ether. These cellulosic polymers have a degree of substitution,
D.S., on the anhydroglucose unit from greater than 0 and up to 3,
inclusive. By "degree of substitution " or "D.S." is meant the average
number of hydroxyl groups originally present on the anhydroglucose unit
comprising the cellulose polymer that are replaced by a substituting
group. Representative fluid-permeable materials are discussed in U.S. Pat.
No. 4,874,388, for example.
First wall section 12a, second wall section 12b and sleeve 30 optionally
comprise a nontoxic plasticizer. Representative plasticizers suitable for
forming wall 12a, wall 12b or sleeve 30 include plasticizers that lower
the temperature of the second-order phase of transition or the elastic
modulus of a composition. Also, the plasticizers increase the workability
of wall 12a, wall 12b or sleeve 30 and their flexibility. Plasticizers
operable for the present purpose include straight-chain and branched-chain
plasticizers, cyclic plasticizers, acrylic plasticizers and heterocyclic
plasticizers. Representative plasticizers are well known in the art.
Delivery device 10 in that portion of its compartment 18 surrounded by
first wall section 12a comprises a beneficial agent 20 that produces a
desired and useful result when administered to a warm-blooded animal,
including humans and farm animals. The beneficial agent 20 is useful in
one embodiment for increasing the rate of growth and the efficiency of
feed utilization in equine, bovine and swine. The beneficial agent 20 in
another embodiment is useful for controlling estrus and ovulation in the
course of breeding farm animals for commercial purposes, for effecting
contraception and for producing an anabolic response associated with the
inhibition of estrus. Beneficial agent 20 in another embodiment is a drug
useful for producing a therapeutic effect. The beneficial agent 20 in yet
other embodiments comprises agents that act at synaptic and neuroeffector
sites, agents acting on the central nervous system, autocoids,
anti-inflammatory agents, analgesics, antiypretic agents, cardiovascular
agents, and the like.
Representative beneficial agents 20 that can be administered by delivery
device 10 include pharmacologically active peptides and proteins, anabolic
hormones, growth promoting hormones, hormones related to the endocrine
system comprising porcine growth promoting hormone, bovine growth
promoting hormone, equine growth promoting hormone, ovine growth promoting
hormone, human growth promoting hormone, growth promoting hormones derived
by extraction and concentration from pituitary and hypothalmus glands,
growth promoting hormones produced by recombinant DNA methods, bovine
growth promoting hormone as described in Nucleic Acid Res., 10:7197
(1982), ovine growth promoting hormone as described in Arch. Biochem,
Biophys., 156:493 (1973), and porcine growth promoting hormone as
described in DNA, 2:37 (1983). The polypeptides also comprise growth
hormone, somatropin, somatotropin, somatotropin analogues, modified
porcine somatotropin, modified bovine somatotropin, derivatives of
somatotropin including both porcine and bovine somatotropin derivatives,
somatomedin-C, gonadotropic releasing hormone, follicle stimulating
hormone, lutenizing hormone, LH-RH, growth hormone releasing factor,
gonadotropin releasing factor, insulin, colchicine, chorionic
gonadotropin, oxytocin, somatotropin plus an amino acid, vasopressin,
adrenocorticotrophic hormone, epidermal growth factor, prolactin,
somatostatin, somatotripin plus a protein, cosyntropin, lypressin,
polypeptides such as thyrotropin releasing hormone, thyroid stimulating
hormone, secretin, pancreozymin, enkephalin, glucagon, endocrine agents
secreted internally and distributed in an animal by way of the
bloodstream, and the like. The beneficial agents and their dosage unit
amounts are known to the prior art in The Pharmacological Basis of
Therapeutics, by Gilman, Goodman, Rall and Murad, 7th Ed., (1985),
MacMillan Publishing Co., N.Y.; in Pharmaceutical Sciences, Remington,
17th Ed., (1985), Mach Publishing Co., Easton, Pa.; and in U.S. Pat. No.
4,526,938. Other useful beneficial agents are discussed in U.S. Pat. No.
4,874,388. Generally, the delivery device 10 comprises from about 5
nanograms to about 20 grams of beneficial agent 20.
Delivery device 10 in its compartment 18 can also comprise pharmaceutical
carrier 21. Carrier 21 comprises beneficial agent 20 and also can comprise
viscosity modulating vehicles, buffers, surfactants, dyes, and other
additives known in the art.
The expandable driving means 25 initially surrounded by second wall section
12b and operable for pushing the beneficial agent composition 20 from
delivery device 10 comprises, in a presently preferred embodiment, an
osmopolymer. The osmopolymers interact with water and aqueous biological
fluids and swell or expand to an equilibrium state. The osmopolymers
exhibit the ability to swell in water and to retain a significant portion
of the imbibed and absorbed water within the polymer structure. The
expandable driving member 25 in another preferred embodiment comprises an
osmagent. The osmagents are known also as osmotically effective solutes
and they are also known as osmotically effective compounds. The
osmotically effective compounds that can be used for the purpose of this
invention include inorganic and organic compounds that exhibit an osmotic
pressure gradient across a semipermeable, i.e. a fluid-permeable, wall.
The expandable driving member 25 yet in another preferred embodiment
comprises an optional osmagent dispersed within the osmopolymer. The
osmagent or osmopolymer can comprise a tablet or a layer or can be pressed
into second wall section 12b. The osmagent or osmopolymer can be in any
suitable form such as particles, crystals, pellets, granules, and the
like, when pressed into a tablet layer and into wall section 12b.
Osmagents and osmopolymers are known to the art in U.S. Pat. Nos.
3,865,108, 4,002,173, 4,207,893, 4,327,725 and 4,612,008, for example.
Partition layer 27, positioned between the beneficial agent composition and
the expandable driving member, is a means for maintaining the separate
identity of the beneficial agent composition and the driving member, for
transmitting the force generated by the driving member against the
beneficial agent composition, and for substantially restricting the
passage of fluid between the beneficial agent composition and the driving
member. Representative materials useful as a partition layer 27 are known
to the art in, for example, U.S. Pat. No. 4,874,388.
The terms "exit means" and "exit passageway", as used herein, comprise
means and methods suitable for the metered release of the beneficial agent
20 from compartment 18 of delivery device 10. The exit means 13 includes
at least one passageway, orifice, or the like, through first wall section
12a for communicating with compartment 18. The expression "at least one
passageway" includes aperture, orifice, bore, pore, porous element through
which the agent can migrate, hollow fiber, capillary tube, porous overlay,
porous insert, and the like. The expression also includes material that
gets discharged, erodes or is leached form the wall int he fluid
environment of use to produce at least one passageway in delivery device
10. Representative materials suitable for forming at least one passageway,
or a multiplicity of passageways, include an erodible poly(glycolic) acid
or poly(lactic) acid member in the wall; a gelatinous filament; poly(vinyl
alcohol); leachable materials such as fluid-removable pore-forming
polysaccharides, salts, or oxides; erodable or dischargable materials such
as natural and synthetic waxes; and the like. The expression includes
structural characteristics that concentrate stress at a precise point in
the wall so that only a small amount of force will induce breakage in the
wall, yielding a passageway through the wall from compartment 18 to the
outside of the device. A passageway or a plurality of passageways can be
formed by leaching a material such as sorbitol, lactose and like
water-soluble solids from the wall. A passageway or passageways can be
formed by the discharge, as a result of the pressure created by the
expandable member for example, of a material such as a wax. The passageway
can have any shape such as round, triangular, square, elliptical, and the
like, for assisting in the metered release of beneficial agent from
delivery device 10. Delivery device 10 can be constructed with one or more
passageways in spaced-apart relations or more than a single surface of a
dosage form. Passageways and equipment for forming passageways are
disclosed in U.S. Pat. Nos. 3,845,770; 3,916,899; 4,063,064; and
4,008,864. Passageways formed by leaching are disclosed in U.S. Pat. No.
4,200,098 and 4,285,987.
Delivery device 10 can be manufactured by standard manufacturing
techniques. In one process, the first wall section 12a and the second wall
section 12b are independently injection molded or extruded into the
desired shape. Protective sleeve 30 can be manufactured as an integral
part of first wall section 12a or, preferably, it is manufactured as a
separate component by, for example, injection molding or extrusion in the
same manner as the wall sections. Then, the first wall section 12a is
filled with the beneficial agent composition. Then, the second wall
section 12b is filled with an expandable driving member or members, and
the partition layer is next added thereto in layered arrangement.
Optionally, the partition layer may be added to the first wall section 12a
after filling the wall section with beneficial agent, in addition to, or
instead of, the partition layer added to second wall section 12b. Next,
the two sections at their open ends are slid together. The union can be
effected by having the opened end of one of the wall sections enlarged for
slidably receiving the end of the other wall section in mated relation to
form an essentially fluid-tight union. In another embodiment, the opened
end of one of the wall sections is made smaller than the end of the other
wall section, and the smaller end is placed in the non-enlarged end to
form a closed system. The two wall sections at their junction are
optionally heat sealed, adhesive sealed, solvent sealed, ultrasonically
sealed, radiofrequency sealed, or spin welded, also known as friction
heating to weld. When protective sleeve 30 is made as a component separate
from first section 12a, it is then slipped over second wall section 12b
and slid over first wall section 12a at the junction of sections 12a and
12b. Protective sleeve 30 and first wall section 12a are joined together
by heat seal, adhesive seal, solvent seal, ultrasonic seal, radiofrequency
seal, or spin weld, for example. Then, at least one passageway is drilled
in the lead end of the manufactured assembly. Alternately, the exit
passageway can be preformed, such as during the injection molding of first
wall section 12a. Optionally, a passageway is drilled or preformed in the
wall and sealed with a break-off tab that is broken open, or cut open, or
the like, at the time of use to connect through the passageway the
beneficial agent composition with the exterior of delivery device 10. Or,
the drilled or preformed passageway is sealed by a material that gets
discharged, leaches, erodes, or dissolves, for example, in the environment
of use.
The delivery device of the present invention can be manufactured for
delivering numerous beneficial agents, including drugs, at a controlled
rate to a presently preferred biological environment of use such as
warm-blooded animals, including humans; ruminants, such as bovines and
sheep; porcines, such as hogs and swine; horses; and the like. The
delivery devices provide for high loading of a beneficial agent and for
its improved delivery in beneficially effective amount over time while
providing resistance to transient mechanical forces. It is to understood
that the delivery devices can take a wide variety of shapes, sizes and
forms adapted for delivering beneficial agents to environments of use. For
example, the devices manufactured as delivery devices can be used for
dispensing a beneficial agent in the anal-rectal passageway, in the
cervical canal, as an artificial gland, in the vagina, as a subcutaneous
implant, and the like. The delivery devices can be used in hospitals,
nursing homes, outpatient clinics, sickrooms, veterinary clinics, farms,
zoos, and other environments of use.
One embodiment of the invention pertains to a method for delivering a
beneficial agent such as a drug to an animal. The method comprises
implanting a delivery device, shaped, sized and adapted as an implant,
into an animal, such as a muscle or an ear thereof. The method comprises
the steps of: (a) admitting into an animal a delivery device of the
present invention; (b) allowing fluid to be imbibed through the
semipermeable second wall section of the delivery device for causing the
expandable driving means to expand and push against the beneficial agent
formulation; and (c) delivering the beneficial agent formulation from the
delivery device by the expandable means increasing in volume at a
controlled rate, thereby pushing the beneficial agent formulation to be
delivered in an effective amount through the exit orifice to the animal
over a prolonged period of time.
DETAILED DESCRIPTION OF EXAMPLES
The following examples are merely illustrative of the present invention and
they should not be considered as limiting the scope of the invention in
any way, as these examples and other equivalents thereof will become
apparent to those versed in the art in the light of the present
disclosure, the drawings and the accompanying claims.
EXAMPLE 1
A delivery device manufactured in the shape of an implantable delivery
device comprising a lead end with an exit passageway and a distant rear
end is manufactured as follows.
First, an expandable driving member is prepared by adding 7.6 kg of water
and 0.4 kg of polyvinyl pyrrolidone to a stainless steel container and
mixing the components for 20 hours to obtain a smooth binder solution.
Next, 10.0 kg of sodium Carbomer.RTM., a sodium salt of polyacrylic acid
polymer, is sized by forcing it through a 0.028 inch mesh screen in a
fluid air mill set at 780-800 rpm speed. Next, 15.0 kg of sodium chloride
is sized by forcing it through a 0.028 inch mesh screen in a fluid air
mill set at 780-800 rpm speed. The 10 kg of screened polymer and the 15 kg
of screened sodium chloride are transferred to the granulator bowl of a
fluid bed granulator, and 6.13 kg of binder solution is slowly sprayed
onto the polymer and the salt in the granulator. The polymer/salt granules
are formed in this manner. These resultant granules are sized through a 16
mesh screen of a Sweco Separator. The amount of granulation from the above
steps is 25.2 kg, and this is transferred to a blender. Then, enough
magnesium stearate, a lubricant, is added to make up 1% of the total
granulation including the lubricant. A total of 0.255 kg of magnesium
stearate is added. All ingredients are mixed for three minutes at 10 rpm
to produce a homogeneous expandable driving composition. The composition
next is pressed into osmotically active tablets in a tablet press at a
pressure of 500 lbs to produce a round, flat-faced 50 mg tablet as an
expandable driving member.
The semipermeable second wall section that surrounds a compartment for
containing the osmotically active tablet is prepared as follows. First,
3.85 kg of cellulose acetate butyrate and 1.15 kg of tributyl citrate are
dry blended in a mixer for 5 minutes. This produces a polymer plasticizer
blend of 77/23 ratio for the rate-controlling semipermeable wall. The
blend is then fed into an injection molder and molded into the
semipermeable second wall section surrounding a compartment with an opened
end for receiving an expandable driving member and for mating the second
section with the lead, first wall section of the delivery device.
Next, the lead, impermeable first wall section of the delivery device is
prepared by adding 5 kg of polycarbonate (Calibre.RTM. 2000 series, Dow
Chemical) to a hopper dryer and drying the polymer at 250.degree. F. for 4
hours. Then the dry polymer is fed into the hopper of an injection molder
with a four-cavity subgated mold designed with an orifice in place and a
break-off tab to open the orifice. This mold is used to injection-mold an
impermeable first wall section surrounding a compartment with an open end
for receiving components and for mating with the semipermeable second wall
member. Next, the break-off tab is removed, and the orifice channel is
sealed with wax in the following manner. First, 142 gm of microcrystalline
wax 180 M and 142 gm of microcrystalline wax X145A are weighed into a
beaker on a hot plate to effect a 50/50 blend of the two waxes. The blend
is then melted and heated and held to 105.degree.-115.degree. C. for the
operation. The lead end (with the orifice channel) is dipped into the
melted wax blend for 20 seconds, then removed from the melted wax and
cooled for at least 20 seconds, and the excess wax is wiped off.
The protective sleeve is prepared by adding 5 kg of polycarbonate
(Lexan.RTM. HP 1, General Electric) to a hopper dryer and drying the
polymer at 250.degree. F. for 4 hours. The dry polymer is fed into a
hopper dryer of an injection molder where a single-cavity hot tip mold is
used to injection mold the protective sleeve with two open ends, one for
mating with the fully assembled delivery device and the other to allow
access of moisture to the semipermeable membrane area. There are also four
ridges to stops spaced circumferentially around the inner wall of the
sleeve.
Next, the elastomeric partition or piston is prepared by injection molding
Santoprene.RTM., a thermoplastic elastomer, into a four-ribbed piston,
weighing approximately 31 mg. Then, the piston is lubricated with silicone
medical fluid 1000 cs to facilitate movement of the piston inside the
device.
The delivery device is assembled by first charging the subassembly
comprising the semipermeable second wall member with two of the osmotic
tablets. Then, the lubricated elastomeric piston is inserted on top of the
osmotic tablets to be flush with the top of the semipermeable walled
member. Next, the delivery device subassembly comprising the substantially
fluid-impermeable first wall member is filled with 340 mg of beneficial
agent formulation at 40.degree. C., wherein the formulation comprised
33.33 wt % (weight percent) porcine somatotropin, 4.53 wt % sodium
phosphate monobasic, 28.47 wt % water, 33.0 wt % glycerol, and 0.67 wt %
Tween-80. Then, the two subassemblies at their opened ends are joined by
inserting partially the second wall section into the first wall section.
Finally, 4 drops of moisture-cured cyanoacrylate adhesive are dropped onto
the remaining exposed surface, and the members are fully inserted and then
twisted to effect a sealed delivery device.
Then, the system is completed by joining the sealed delivery device
described above with the protective sleeve. These two are joined by
partially inserting the protective sleeve over the glue junction of the
sealed system. Next, 4 drops of moisture-cured cyanoacrylic adhesive are
dropped onto the remaining exposed surface of the junction, and the sleeve
is fully inserted until the molded-in stop on the inside of the protective
sleeve is reached. The members are twisted to effect a sealed, fully
protected delivery device.
EXAMPLE 2
Two delivery devices with protective sleeves prepared as in Example 1 and
five prior art devices that are identical to the two sleeved devices but
without the protective sleeve were hydrated for six weeks and were then
subjected to a radially applied force of 100 mm/min in an Instron.RTM. at
the junction of the water-impermeable and the water-permeable wall
portions of the device. The mean maximum load applied to the systems prior
to breakage was determined: 2.2 kg.sub.f for the sleeveless systems and
6.2 kg.sub.f for the sleeved systems.
EXAMPLE 3
Delivery devices with protective sleeves were tested in vivo in comparison
with prior art devices without sleeves, as follows.
The base of the ear of a finishing hog was disinfected, and a delivery
device prepared as in Example 1 either with or without the protective
sleeve was implanted into the ear with the orifice of the delivery device
oriented up, using a modified trocar implanting device. The hogs were
weighed on a weekly basis, and feed intake was monitored. Hogs without any
implant served as controls. There were 40 hogs per treatment, and the hogs
were held in pens, with 5 hogs per pen. The average daily weight gain was
computed, as was fed consumption and feed efficiency. At the end of 6
weeks, the implants were retrieved from the live hogs using local
anesthetic. The explanted delivery devices were examined for piston travel
(which correlates to the cumulative amount of beneficial agent released)
and for overall condition (such as breakage or swelling of the
semipermeable membrane). Two separate studies were run, Study I and Study
II, and results from these two studies are presented below in Tables A, B
and C.
Additional studies following the above procedure were run with unsleeved
prior art implants only, and the pooled distribution of delivery rates
(correlated from the distance of piston travel) for all the studies
(Studies I and II and the prior art implant studies) is presented in Table
D below.
The feed efficiency is determined by dividing the pounds of feed consumed
by the number of pounds gained.
TABLE A
______________________________________
6 WEEK PERFORMANCE RESPONSES - STUDY I
Cumulative
Cumulative Cumulative
Avg. Daily
Feed Feed
Treatment Gain Consumption
Efficiency
______________________________________
Control 0.71 2.77 3.91
Without Sleeve
0.70 2.25 (17%) 3.35 (14%)
With Sleeve
(0.012 in*) 0.77 2.46 (11%) 3.21 (18%)
(0.020 in*) 0.74 2.34 (16%) 3.10 (19%)
(0.020 in* + holes )
0.72 2.25 (19%) 3.08 (19%)
______________________________________
*thickness of the sleeve wall
holes (or fluid passage means) present in the sleeve wall
percent improvement over the control
TABLE B
______________________________________
6 WEEK PERFORMANCE RESPONSES - STUDY II
Cumulative Cumulative Cumulative
Avg. Daily Feed Feed
Treatment Gain Consumption Efficiency
______________________________________
Control 0.77 3.23 4.20
Without Sleeve
0.81 2.87 (11%) 3.55 (15%)
With Sleeve
0.81 2.73 (15%) 3.40 (19%)
(0.020 in)*
______________________________________
*thickness of the sleeve wall
percent improvement over the control
TABLE C
______________________________________
PHYSICAL CONDITION OF IMPLANTS
Total Pumps % %
Implant Recovered Broken Swollen
______________________________________
Without Sleeve
I* 39 15.4 0
II 35 17.1 2.8
Total 74 16.2 1.4
With Sleeve
I 113 0 1.3
II 39 0 7.7
Total 152 0 3.3
______________________________________
*Study number
TABLE D
__________________________________________________________________________
DISTRIBUTION OF DELIVERY RATES AT 6 WEEKS
Total Pumps
Distance of Piston Travel (mm)
Implant
Recovered
0 1-5 6-10
11-15
16-20
21-24
25-29
.gtoreq.30
__________________________________________________________________________
No Sleeve
644 1.9%*
2.5%
2.5%
3.7% 5.0% 5.1% 70.3%
9.0%
Sleeve 152 0.6% 0%
0.6%
0.6% 2.6% 3.3% 91.4%
0.6%
__________________________________________________________________________
*% of total pumps recovered
The novel devices of this invention use means for the obtainment of precise
release rates in the environment of use while simultaneously maintaining
the integrity of the device. The protective sleeve according to the
invention provides substantially less breakage and malfunction of the
delivery devices, with a resulting greatly improved delivery of the
beneficial agent, While there has been described and pointed out features
of the invention as applied to presently preferred embodiment, those
skilled in the art will appreciate that various modifications, changes,
additions and omissions in the devices illustrated and described can be
made without departing from the spirit of the invention.
Top